The proposed studies will involve a continuation of the ongoing interest of this laboratory in the cholesterol feedback system and its consistent loss in all hepatomas, leukemia and probably other tumors as well. Having localized this defect to the enzymatic site of conversion of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA) to mevalonate, studies of a possible defect in this enzyme or its response to exogenous cholesterol in the tumor cell will be investigated. The loss of feedback control of HMG CoA reductase in tumors leads to the uncontrolled production of mevalonic acid; we have, therefore, studied the metabolic fate of circulating mevalonate and have found that unexpectedly this cholesterol precursor, once it reaches the bloodstream, is metabolized both to sterols and to CO2 primarily in the kidneys rather than in the liver. We propose to extend this observation by determining whether malignancy alters the ability of kidney cells to metabolize mevalonic acid. Mevalonic acid conversion to sterols will be examined in tissue slices from three types of hypernephroma. The ability of renal tumors to accumulate and metabolize mevalonate in vivo will likewise be evaluated. This project will also be directed at determining the underlying cause of the loss of the cholesterol feedback system in various tumors. Studies using tissue culture of embryonic chicken liver and hepatoma cells will be employed to determine whether loss of cholesterol feedback control involves defective binding of a lipoprotein cholesterol carrier to the plasma membrane of the cell; and whether cancer cells have a defective synthesis or breakdown of B-hydroxy-B-methylglutaryl coenzyme A reductase.